Pregnancy-induced hypertension (PIH) is a major cause of death in pregnant and parturient women in addition to bleeding, obstetrical pulmonary embolus, and the like. A method for managing PIH is still an important issue for obstetricians. However, the cause and morbidity of PIH remain unknown. Furthermore, the definition and classification of PIH have not yet been unified worldwide. In Japan, PIH is defined by the presence of at least one of hypertension, proteinuria, and edema as symptoms during pregnancy, where these symptoms are not simple accidental complications of pregnancy. However, hypertension is absolutely the major symptom that indicates PIH. A case in which edema alone is exhibited is not said to be PIH. PIH is found in approximately 10% of pregnant women (6% to 14%).
PIH is classified into early onset type (onset before pregnancy week 32) and late onset type (onset at and after pregnancy week 32) depending on the onset timing. Classification of PIH in terms of severity is as follows. A case in which one or more of hypertension, proteinuria, and edema as symptoms are exhibited, which are all determined to be mild, is determined to constitute mild-type PIH. A case in which at least one of these symptoms, which is determined to be severe, is exhibited is determined to constitute severe-type PIH. In both early onset type and severe-type PIH, organ damage becomes rapidly worse in both the mother and the fetus, so that prognosis is bad. Thus, these types of PIH require strict management.
PIH is diagnosed by examining the symptoms of hypertension, proteinuria, and edema. Specifically, hypertension is determined to exist when systolic blood pressure is 140 mmHg or more and diastolic blood pressure is 90 mmHg or more. Furthermore, proteinuria is determined to exist when 30 mg/dL or more protein is detected in 24 hour urine specimen by Esbach's method or a measurement method according thereto. Edema is determined to exist when a tibial crest remains depressed after digital compression and body weight gain of 500 g or more is observed during the most recent 1 week of pregnancy. When at least one of these symptoms is observed, a diagnosis of PIH is made (edited by Shoichi Sakamoto, et al., Pregnancy-induced hypertension, Principles of Obstetrics and Gynecology 2: MEDICAL VIEW CO., LTD., 1998: 340-60).
Furthermore, a general PIH case leads to decreased circulating blood volume and is associated with hemoconcentration. Thus, plasma protein concentration may also be measured. Furthermore, severe PIH often leads to microthrombus formation that indicates an elevated state of the coagulation system and the same with respect to the secondary fibrinolytic system. Thus, factors involved in such coagulation-fibrinolytic system, such as blood platelets and D-dimer, are also examined. Furthermore, lipids, hepatic functions, and the like are also tested if necessary (edited by Shoichi Sakamoto et al., Pregnancy-induced hypertension. Principles of Obstetrics and Gynecology 2: MEDICAL VIEW CO., LTD. 1998: 340-60).
Management of a patient with PIH and therapeutic methods therefore vary depending on severity. However, the severity of PIH is currently determined comprehensively by a combination of the above-described plurality of testing methods. Therefore, establishment of a method for conveniently and objectively determining severity is desired. Moreover, it is thought that the influence of PIH can be substantially suppressed by strict management when PIH is found at the initial stage. However, detection of PIH at the initial stage is difficult via any of the above-described testing methods. Currently, no indicator for predicting the onset of PIH has been established.
Furthermore, when PIH becomes more severe, placental functions will decrease and the nutritional and oxygen conditions of a fetus will be worse. Determination of such functions is very important in determination of delivery timing for a fetus. Accordingly, a precise indicator for evaluating fetuses and placental functions is desired.
Human lipocalin-type prostaglandin D synthase (hereinafter, L-PGDS) is an enzyme that catalyzes isomerization from PGH2, which is a common precursor of various prostaglandins, to PGD2. L-PGDS is a multifunctional protein because it also has a function of transporting small hydrophobic molecules (Urade Y. et al., Prostaglandin D synthase: Structure and Function. Vitam Horm 2000; 58: 89-120). It has been reported that elevated blood L-PGDS levels(concentrations) are detected in patients with advanced renal disease (Hoffmann A. et al., Molecular Characterization of β-trace Protein in Human Serum and Urine: A Potential Diagnostic Marker for Renal Diseases. Glycobiology 1997; 7: 499-506). Furthermore, the present inventors have revealed that L-PGDS levels are increased in the body fluids of patients with early renal disease (before the progression of renal disease) (Hamano K. et al., Blood Sugar Control Reverses the Increase in Urinary Excretion of Prostaglandin D Synthase in Diabetic Patients. Nephron 2002; 92: 77-85). The present inventors have also revealed that L-PGDS is produced in atherosclerotic plaque and that L-PGDS levels are increased in the body fluids of patients with coronary artery disease (Eguchi Y. et al., Expression of Lipocalin-Type Prostaglandin D Synthase (β-trace) in Human Heart and its Accumulation in the Coronary Circulation of Angina Patients. Proc Natl Acad Sci U.S.A. 1997; 94: 14689-94). As described above, the relationship between L-PGDS and renal disease or vascular lesion has been revealed. However, the relationship between L-PGDS and PIH has net yet examined.
Non-patent document 1: Hoffmann A. et al., Glycobiology 1997; 7: 499-506
Non-patent document 2: Hamano K. et al., Nephron 2002; 92: 77-85
Non-patent document 3: Eguchi Y. et al., Proc Natl Acad Sci U.S.A. 1997; 94: 14689-94